This work focuses on enterotoxigenic Escherichia coli (ETEC), globally the most common bacterial cause of serious diarrheal illness. These illnesses threaten the lives of many children in poor regions of the world where sanitation and clean water are limited. While it has long been known that prior infections with these organisms offer protection against later infection, the nature of the protection is not known. The long-term goal o these studies is to address very basic questions that have eluded ETEC investigators trying to develop vaccines for these organisms: 1.To what proteins do infected people mount antibody responses after infection? 2. Which of these responses appear to be associated with protection against ETEC? 3. Can we show that these proteins trigger protective immune responses in a vaccine? Studies to date have shown us that the immune response following ETEC infection is actually quite complicated, with recognition of many proteins. Some novel proteins that are not part of vaccines currently being tested could be added to improve the coverage and function of these vaccines. The basic goals of this proposal are to accelerate the discovery of novel protective proteins and to translate their use into effective ETEC vaccine components. Addressing these fundamental questions will fill important gaps in our understanding of protective immune responses that develop following ETEC infections, and permit a more rational approach to development of a broadly protective vaccine for these pathogens of global importance.